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1.
Med Sci Monit ; 26: e919815, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32248203

RESUMO

BACKGROUND Fructus aurantii is a flavonoid derived from Citrus aurantium (bitter orange) that is used in traditional Chinese medicine (TCM) to treat gastric motility disorders. This study aimed to investigate the effects of low-dose and high-dose decoctions of Fructus aurantii in a rat model of functional dyspepsia (FD). MATERIAL AND METHODS Sprague-Dawley rats (n=90) were divided into nine study groups: the control group, the FD model group, the domperidone-treated (Domp) group, the low-dose raw Fructus aurantii (FA-L) group, the high-dose raw Fructus aurantii (FA-H) group, the low-dose Fructus aurantii with stir-fried wheat bran (Bran-L) group, the high-dose Fructus aurantii with stir-fried wheat bran (Bran-H) group, the low-dose Fructus aurantii with stir-fried wheat bran and honey (Honey-L) group, and the high-dose Fructus aurantii with stir-fried wheat bran and honey (Honey-H) group. The FD rat model was established by semi-starvation, followed by tail damping, stimulation, and forced exercise with fatigue. Change in weight, rate of gastric emptying and intestinal propulsion, and serum levels of leptin, motilin, vasoactive intestinal peptide (VIP), gastrin, calcitonin gene-related peptide (CGRP), ghrelin, and cholecystokinin were compared between the groups. RESULTS In the FD model group, weight, rate of gastric emptying and intestinal propulsion significantly decreased, the expression of leptin, VIP and CGRP increased, and expression of motilin, gastrin, ghrelin, and cholecystokinin significantly decreased. Treatment with low-dose Fructus aurantii with stir-fried wheat bran significantly reversed these effects. CONCLUSIONS In the rat model of FD, low-dose Fructus aurantii with stir-fried wheat bran increased gastrointestinal motility and gastrointestinal hormone levels.


Assuntos
Citrus/química , Dispepsia/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Medicina Tradicional Chinesa , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
2.
Am J Physiol Gastrointest Liver Physiol ; 318(4): G682-G693, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003602

RESUMO

Postprandial dyslipidemia is a common feature of insulin-resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. Although bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here, we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions, and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA (but not DCA) effects were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the antidiabetic hormone glucagon-like peptide-1 (GLP-1). Although the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate-limiting enzyme for bile acid synthesis. Bile acid signaling may be an important mechanism of controlling dietary lipid absorption, and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia.NEW & NOTEWORTHY We present new data suggesting potentially important roles for bile acids in regulation of postprandial lipid metabolism. Specific bile acid species, particularly secondary bile acids, were found to markedly inhibit absorption of dietary lipid and reduce postprandial triglyceride excursion. These effects appear to be mediated via bile acid receptors, farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Importantly, bile acid signaling may trigger glucagon-like peptide-1 (GLP-1) secretion, which may in turn mediate the marked inhibitory effects on dietary fat absorption.


Assuntos
Ácido Desoxicólico/farmacologia , Hiperlipidemias/tratamento farmacológico , Isoxazóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Período Pós-Prandial , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Exenatida/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/sangue , Mucosa Intestinal , Intestinos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/agonistas , Ácido Taurocólico/farmacologia
3.
Am J Physiol Gastrointest Liver Physiol ; 318(4): G635-G645, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036693

RESUMO

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [-11% (-16, -4), P = 0.004]; and FD [-8% (-9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying.NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.


Assuntos
Dispepsia/tratamento farmacológico , Esvaziamento Gástrico/efeitos dos fármacos , Secretina/farmacologia , Adulto , Estudos Cross-Over , Sacarose na Dieta , Método Duplo-Cego , Feminino , Alimentos Formulados , Humanos , Masculino , Refeições , Pessoa de Meia-Idade , Período Pós-Prandial , Saciação
5.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R263-R273, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774306

RESUMO

The rate of gastric emptying and the release of gastrointestinal (GI) hormones are major determinants of postprandial blood-glucose concentrations and energy intake. Preclinical studies suggest that activation of GI bitter-taste receptors potently stimulates GI hormones, including glucagon-like peptide-1 (GLP-1), and thus may reduce postprandial glucose and energy intake. We evaluated the effects of intragastric quinine on the glycemic response to, and the gastric emptying of, a mixed-nutrient drink and the effects on subsequent energy intake in healthy men. The study consisted of 2 parts: part A included 15 lean men, and part B included 12 lean men (aged 26 ± 2 yr). In each part, participants received, on 3 separate occasions, in double-blind, randomized fashion, intragastric quinine (275 or 600 mg) or control, 30 min before a mixed-nutrient drink (part A) or before a buffet meal (part B). In part A, plasma glucose, insulin, glucagon, and GLP-1 concentrations were measured at baseline, after quinine alone, and for 2 h following the drink. Gastric emptying of the drink was also measured. In part B, energy intake at the buffet meal was quantified. Quinine in 600 mg (Q600) and 275 mg (Q275) doses alone stimulated insulin modestly (P < 0.05). After the drink, Q600 and Q275 reduced plasma glucose and stimulated insulin (P < 0.05), Q275 stimulated GLP-1 (P < 0.05), and Q600 tended to stimulate GLP-1 (P = 0.066) and glucagon (P = 0.073) compared with control. Quinine did not affect gastric emptying of the drink or energy intake. In conclusion, in healthy men, intragastric quinine reduces postprandial blood glucose and stimulates insulin and GLP-1 but does not slow gastric emptying or reduce energy intake under our experimental conditions.


Assuntos
Bebidas , Glicemia/efeitos dos fármacos , Alimentos Formulados , Esvaziamento Gástrico/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Quinina/administração & dosagem , Paladar/efeitos dos fármacos , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Método Duplo-Cego , Ingestão de Energia , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Voluntários Saudáveis , Humanos , Insulina/sangue , Masculino , Período Pós-Prandial , Fatores de Tempo , Adulto Jovem
6.
PLoS One ; 14(12): e0226065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31805134

RESUMO

The objectives of this study were to assess gastrointestinal transit times, sedation, and signs of nausea associated with intravenous lidocaine infusions in dogs following targeted acupuncture at Pericardium-6 (PC6) and Stomach-36 (ST36). In a randomized, blind crossover design, 6 healthy, adult Beagles were fed thirty 1.5 mm barium-impregnated polyethylene spheres (BIPS), then were subject to 30 minutes of: 1) no acupuncture, 2) bilateral targeted acupuncture at PC6 and ST36, or 3) bilateral non-target acupuncture at Lung-5 (LU5) and Bladder-55 (BL55). Lidocaine was immediately administered at 1 mg/kg intravenously followed by 50 µg/kg/min. BIPS were tracked radiographically; sedation and nausea were scored at baseline (Time 0) and for 11 hours during lidocaine infusions. Transit times and sedation and nausea scores were analyzed with a linear mixed-effects model; the number of BIPS at defined time points was analyzed with a piecewise linear mixed-effects model. All P values were two-sided and P < 0.05 was considered significant. Sedation and nausea scores did not differ between treatments at any time point (all P > 0.05). However, nausea scores in all groups were significantly greater at Times 5 through 7 and at Time 11 compared to Time 0 whereas sedation scores in all groups were significantly greater at Times 2 through 11 compared to Time 0 (all P < 0.05). The number of BIPs found out of the stomach, the number found in the large intestine, gastric emptying and gastrointestinal transit times did not differ between treatments (all P > 0.05). Acupuncture at PC6 and ST36 did not alleviate nausea and sedation associated with lidocaine infusions in clinically normal animals or affect gastric emptying and gastrointestinal transit.


Assuntos
Pontos de Acupuntura , Terapia por Acupuntura , Sedação Consciente , Motilidade Gastrointestinal/efeitos dos fármacos , Lidocaína/administração & dosagem , Lidocaína/efeitos adversos , Náusea/induzido quimicamente , Animais , Cães , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Infusões Intravenosas , Masculino , Náusea/diagnóstico por imagem , Náusea/prevenção & controle , Radiografia
7.
Diabetes Res Clin Pract ; 158: 107892, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31669625

RESUMO

AIMS: Glucagon has an important role in glucose homeostasis. Recently, a new plasma glucagon assay based on liquid chromatography-high resolution mass spectrometry was developed. We evaluated the influence of a dipeptidyl peptidase-4 inhibitor (anagliptin) on plasma glucagon levels in Japanese patients with type 2 diabetes by using this new assay. METHODS: Twenty-four patients with type 2 diabetes were enrolled in a prospective, single-center, randomized, open-label study and were randomly allocated to 4 weeks of treatment with metformin (1000 mg/day) or anagliptin (200 mg/day). A liquid test meal labeled with sodium [13C] acetate was ingested before and after the treatment period. Samples of blood and expired air were collected over 3 h. Plasma levels of glucose, glucagon, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured, and gastric emptying was also evaluated. RESULTS: Twenty-two patients completed the study (metformin group: n = 10; anagliptin group: n = 12). Glycemic control showed similar improvement in both groups. In the anagliptin group, there was a slight decrease of the incremental area under the plasma concentration versus time curve for glucagon after the test meal (P = 0.048). In addition, the plasma level of active GLP-1 and GIP was increased, and plasma C-peptide was also increased versus baseline. Neither anagliptin nor metformin delayed gastric emptying. CONCLUSIONS: In patients with type 2 diabetes maintained endogenous insulin secretion, anagliptin increased the plasma level of active GLP-1 and GIP in association with a slight stimulation of insulin secretion and slight inhibition of glucagon secretion, but did not delay gastric emptying. Clinical Trial Registry: University hospital Medical Information Network UMIN000028293.


Assuntos
Esvaziamento Gástrico/efeitos dos fármacos , Glucagon/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Espectrometria de Massas/métodos , Metformina/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Estudos Prospectivos , Pirimidinas/farmacologia , Adulto Jovem
8.
Nutrients ; 11(11)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694157

RESUMO

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.


Assuntos
Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Galactanos/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mananas/farmacologia , Gomas Vegetais/farmacologia , Proteínas do Soro do Leite/farmacologia , 3-O-Metilglucose/sangue , Idoso , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Insulina/sangue , Intestino Delgado/metabolismo , Masculino , Período Pós-Prandial/efeitos dos fármacos
9.
Pak J Pharm Sci ; 32(4): 1723-1747, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608897

RESUMO

Curcumin, a natural polyphenolic compound derived from turmeric (Curcuma longa L), has proven to exhibit biological activity towards different kinds of diseases. But the low oral bioavailability results in a limited application in clinic treatment. Recently, numerous curcumin derivatives were synthesized by the modification of three important functional groups: The aromatic o-methoxy phenolic group, a seven conjugated carbon linker and the ß-diket one moiety. However, many people know curcumin only as an anticancer agent and overlook the diverse biological activities of curcumin and curcumin-based derivatives. In this article, we summarized the novel synthetic curcuminoids by different therapeutic activities including antioxidant activity, anti-HIV activity, stimulating activity of gastric emptying, anti-inflammatory activity, ACE inhibition activity, prevention of Parkinson's disease, anti-parasitism, anti-obesity, prevention of Alzheimer's disease, and antibacterial activity. The relation between structural features and activities were also investigated.


Assuntos
Fármacos Anti-HIV/farmacologia , Antioxidantes/farmacologia , Antiparkinsonianos/farmacologia , Diarileptanoides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Fármacos Anti-HIV/química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Antioxidantes/química , Antiparkinsonianos/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Diarileptanoides/síntese química , Diarileptanoides/química , Esvaziamento Gástrico/efeitos dos fármacos , Humanos , Estrutura Molecular
10.
Biomed Pharmacother ; 120: 109442, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546083

RESUMO

AIM: To evaluate whether Xiaoerfupi (XEFP), a traditional Chinese medicine formula, can ameliorate functional dyspepsia (FD) through regulation of the HTR3A and c-FOS. METHOD: The FD rat model was established through administration of iodoacetamide (IA) and interval fasting. XEFP group rats received XEFP for 3 weeks. Detection of gastric emptying and gastrin were performed to assess the interventional effect of XEFP. The constituents of XEFP were submitted to BATMAN-TCM, an online bioinformatics analysis tool, to predict the targets related to dyspepsia. Furthermore, the prediction was validated via Western blot assay. RESULTS: XEFP enhanced gastric emptying of rats (XEFP middle dose vs. FD model: 71.87 ±â€¯15.21% vs. 30.07 ±â€¯12.76%, P <  0.01) and simultaneously increased gastrin in FD rats (XEFP middle dose vs. FD model: 63.61 ± 17.90 vs. 26.14 ± 7.78 pg/ml, P <  0.01). KEGG enrichment analysis revealed that the neuroactive ligand-receptor interaction was successfully enriched (P-value = 2.2E-13, Benjamini = 2.0E-11). Combining different Bioinformatics analysis implied that XEFP regulates HTR3A and c-FOS. Subsequently molecular biological studies confirmed that the expression of HTR3A and c-FOS in the model group was upregulated in rats in comparison with the control group. Furthermore, the expression of HTR3A and c-FOS in the XEFP group (middle dose) compared with the model group was significantly reduced (P <  0.01). CONCLUSION: XEFP may ameliorate FD through regulation of the HTR3A and c-FOS.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Dispepsia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Animais , Dispepsia/patologia , Esvaziamento Gástrico/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
11.
Eur J Pharm Sci ; 138: 105019, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374253

RESUMO

Enteric coating is a common procedure in the development of oral pharmaceutical dosage forms. The main advantage of enteric coating is that it protects the drug from acidic pH and enzymatic degradation in the stomach while protecting it from the undesirable effects of some drugs. There is certain controversy regarding the real influence of enteric coating on the bioavailability of many drugs. Various scientific articles have demonstrated an improvement in the extent of bioavailability of some drugs when enteric coating is used. In recent years, there have been many studies examining different formulation strategies for monolithic and multiparticulate systems, including different pharmaceutical oral dosage forms and delivery systems based on the combined use of enteric coating and other methods that improve the bioavailability of drugs administered orally. However, the real bioavailability, serum levels and therapeutic effect of these drugs may be influenced by gastrointestinal pH values, gastrointestinal environment, inter-individual or intra-individual variability in gastric emptying and gastrointestinal transit time, interpatient variability associated with the type of polymer used for enteric coating or other formulation variables. It deserves special attention to know the real influence of enteric coating on the bioavailability of new oral dosage forms.


Assuntos
Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Administração Oral , Disponibilidade Biológica , Química Farmacêutica/métodos , Formas de Dosagem , Sistemas de Liberação de Medicamentos/métodos , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos
12.
Life Sci ; 233: 116749, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412264

RESUMO

AIMS: Functional dyspepsia (FD) is very common worldwide with a high prevalence of 10%-30%, and it becomes a heavy burden to patients because of its hard to be cured. In our previous study, phenylethanoid glycosides were found to exist in Houpo, a traditional Chinese medicine commonly used for the treatment of abdominal distention, pain and dyspepsia. In the present study, the effect of magnoloside A (MA), a main phenylethanoid glycoside in Houpo, on FD was firstly evaluated and its potential mechanism was concluded. MATERIALS AND METHODS: MA was orally administered consequently for 3 weeks, and its effect on a FD rat model established through transient neonatal gastric irritation and mature alternate-day fasting was tested. Levels of brain-gut peptides and inflammatory factors in blood or tissues were determined by ELISA methods. Meanwhile, the gut microbiota was analyzed by 16S rRNA gene sequencing and short chain fat acids were determined by GC/MS. KEY FINDINGS: MA exhibited anti-FD activities by fastening the delayed gut emptying rate of FD rat and increasing the levels of gastrin, motilin, and calcitonin gene related protein; and decreasing the levels of 5-hydroxytryptamine, nitric oxide synthase, and vasoactive intestinal peptide. On the other hand, MA can modulate the composition of gut microbiota, resulting in the variation of the short chain fat acids. SIGNIFICANCE: MA ameliorated FD rats by modulating of the secretion of related brain-gut peptides and altering the composition of intestinal microbiota.


Assuntos
Encéfalo/metabolismo , Dispepsia/tratamento farmacológico , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Glicosídeos/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Administração Oral , Animais , Animais Recém-Nascidos , Dispepsia/metabolismo , Dispepsia/microbiologia , Esvaziamento Gástrico/efeitos dos fármacos , Glicosídeos/química , Magnolia/química , Masculino , Álcool Feniletílico/química , Ratos , Ratos Sprague-Dawley
13.
Expert Rev Gastroenterol Hepatol ; 13(8): 711-721, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31314613

RESUMO

Introduction: Gastroparesis is a chronic disorder of the stomach characterized by delayed gastric emptying without mechanical obstruction. Diabetes is the most commonly known cause of gastroparesis. Management of diabetic gastroparesis involves lifestyle modifications, glycemic control, pharmacological drugs, and for refractory cases surgical treatments. Metoclopramide remains the only drug approved by the Food and Drug Administration for diabetic gastroparesis. The aim of this article is to provide a concise review of the pharmacology, clinical efficacy and tolerability of metoclopramide. Areas covered: We searched PubMed using the key words 'metoclopramide', 'diabetic gastroparesis', and 'gastric emptying'. The relevant articles and their bibliography were reviewed. Metoclopramide acts on several different receptors; primarily as a dopamine receptor antagonist, both peripherally improving gastric emptying, and centrally resulting in an anti-emetic effect. Metoclopramide side effects, mostly related to its ability to cross the blood-brain barrier, include drowsiness, restlessness, hyperprolactinemia, and tardive dyskinesia (TD), a movement disorder that may be irreversible. Expert opinion: Metoclopramide carries a black box warning for use >12 weeks due to the risk of TD. However, gastroparesis patients experience chronic symptoms often requiring prolonged treatments. Physicians and patients look forward to FDA approval of new agents for gastroparesis with better efficacy and safety profile.


Assuntos
Complicações do Diabetes/complicações , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Esvaziamento Gástrico/efeitos dos fármacos , Gastroparesia/tratamento farmacológico , Metoclopramida/uso terapêutico , Trato Gastrointestinal Superior/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/efeitos adversos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Gastroparesia/etiologia , Humanos , Metoclopramida/efeitos adversos , Metoclopramida/farmacologia , Resultado do Tratamento , Trato Gastrointestinal Superior/inervação
14.
Am J Gastroenterol ; 114(8): 1265-1274, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31295161

RESUMO

OBJECTIVES: Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis. METHODS: Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test. RESULTS: Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup. DISCUSSION: In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.


Assuntos
Benzofuranos/uso terapêutico , Gastroparesia/tratamento farmacológico , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Adulto , Testes Respiratórios , Estudos Cross-Over , Método Duplo-Cego , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Humanos , Masculino , Qualidade de Vida , Índice de Gravidade de Doença
15.
BMC Complement Altern Med ; 19(1): 159, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277639

RESUMO

BACKGROUND: Delayed gastric emptying play an important role in the pathology of functional dyspepsia. Owing to their functional attributes in alleviating the gastrointestinal disorders, single or polyherbal formulations have gained attention to treat the symptoms of functional dyspepsia. We have investigated the safety and efficacy of a novel formulation of Ferula asafoetida oleo resin and standardized Silybum marianum extract (Asdamarin). METHODS: The effect of asdamarin on delayed gastric emptying was investigated in Sprague Dawley rats using phenol red method. The acute and sub-acute oral toxicity was evaluated in wistar rats following OECD guidelines 425 and 407 respectively. The data were analyzed by one-way ANOVA using GraphPad Prism 5.0 software. RESULTS: Oral administration of Asdamarin dose-dependently improved the delay in gastric emptying as evident from the significant increase in the gastrointestinal transit time (p < 0.001). The LD50 of asdamarin was estimated to be more than 2000 mg/kg. Further, in the 28-day sub-acute toxicity study, the administration of 250, 500 and 1000 mg/kg of Asdamarin did not significantly altered the feed and water consuption, body weight change, biochemical and haematological parameters compared to control animals. Macroscopic and histopathological examination of vital organs revealed no toxic signs. CONCLUSION: The preliminary data from the present study provides the first evidence on the possible effectiveness of novel formulation of F. Asafoatida and S. marianum extracts in alleviating the associated symptoms of functional dyspepsia. The toxicity data indicated that Asdamarin can be considered safe up to 1000 mg/kg dose.


Assuntos
Dispepsia/tratamento farmacológico , Ferula/toxicidade , Esvaziamento Gástrico/efeitos dos fármacos , Cardo-Mariano/toxicidade , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Fitoterapia , Ratos Sprague-Dawley , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
16.
Curr Opin Crit Care ; 25(4): 349-355, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31247631

RESUMO

PURPOSE OF REVIEW: This review provides an update of recently conducted studies and randomized controlled trials evaluating prokinetic drugs. RECENT FINDINGS: Prokinetic drugs accelerate gastric emptying and, particularly in patients with gastric dysmotility and enteral feed intolerance, their use increases the delivery of enteral nutrition. However, prokinetic drugs have not been shown to improve patient-centered outcomes in trials but benefit is assumed on the basis of observational studies, which report close associations between gastric dysmotility, enteral feed intolerance and poor outcomes, and improvement in surrogate physiological outcomes when prokinetic drugs are administered. SUMMARY: It may not be feasible to establish superiority of a prokinetic drug within a randomized controlled trial with a patient-centered event as the primary outcome. The use of metoclopramide and erythromycin as prokinetic drugs is based on observations from trials measuring surrogate physiological outcomes. Randomized controlled trials of alternative drug regimens and novel prokinetic drugs have recently been completed and results outlined.


Assuntos
Eritromicina/uso terapêutico , Esvaziamento Gástrico/efeitos dos fármacos , Fármacos Gastrointestinais/uso terapêutico , Metoclopramida/uso terapêutico , Nutrição Enteral , Humanos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Medicine (Baltimore) ; 98(20): e15669, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096498

RESUMO

BACKGROUND: Preoperative oral carbohydrate (POC) has been recommended as an important element of the enhanced recovery after surgery (ERAS) protocol, but its effect on patients undergoing endoscopic submucosal dissection (ESD) remains unclear. Our study aims to investigate the effects of POC for ESD surgery, with particular focus on perioperative well-being and gastric peristalsis. METHODS: A prospective, randomized, and controlled study of patients undergoing ESD was conducted. Seventy-three patients were assigned to 2 groups: experiment (36 patients) and control (37 patients). The experiment group received oral carbohydrate solution 710 mL the night before and 355 mL 2 hours prior to operation. The control group fasted for 10 hours prior to operation. Gastric empty assessment, peristaltic score, and operation score were measured. In addition, visual analogue scale (VAS) scores for 6 parameters (thirst, hunger, mouth dryness, nausea, vomit, and weakness) of wellbeing were compared perioperatively. Preoperative basic conditions of patients, postoperative complications, and their clinical outcomes were also recorded. RESULTS: Before anesthesia induction, gastric sonography score was higher in experiment group, while sucked fluid by gastroscopy was similar between 2 groups. And no patient had regurgitation. Moreover, gastric peristaltic score and operation score before operation were both lower in experiment group. Importantly, VAS scores for 3 parameters (thirst, hunger, and mouth dryness) were significantly lower in experiment patients. In addition, clinical outcomes including first time exhaust, first time for drinking water, the usage of hemostasis, postoperative complication, lengths of hospital stay, and in-hospital expense were not significantly different between 2 groups. CONCLUSIONS: Oral administration of carbohydrates preoperatively instead of fasting improves the feelings of thirst, hunger, and mouth dryness in patients following ESD surgery without enhancing risk of regurgitation. And, avoiding preoperative fasting with POC can decrease the degree of gastric peristalsis that may facilitate the successful completion of ESD surgery.


Assuntos
Carboidratos/administração & dosagem , Ressecção Endoscópica de Mucosa/métodos , Cuidados Pré-Operatórios/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia Geral , Jejum , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Nível de Saúde , Preços Hospitalares , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Peristaltismo/efeitos dos fármacos , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Adulto Jovem
18.
Intensive Care Med ; 45(5): 647-656, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31062046

RESUMO

PURPOSE: Enteral feeding intolerance (EFI) is a frequent problem in the intensive care unit (ICU), but current prokinetic agents have uncertain efficacy and safety profiles. The current study compared the efficacy and safety of ulimorelin, a ghrelin agonist, with metoclopramide in the treatment of EFI. METHODS: One hundred twenty ICU patients were randomized 1:1 to ulimorelin or metoclopramide for 5 days. EFI was diagnosed by a gastric residual volume (GRV) ≥ 500 ml. A volume-based feeding protocol was employed, and enteral formulas were standardized. The primary end point was the percentage daily protein prescription (%DPP) received by patients over 5 days of treatment. Secondary end points included feeding success, defined as 80% DPP; gastric emptying, assessed by paracetamol absorption; incidences of recurrent intolerance (GRV ≥ 500 ml); vomiting or regurgitation; aspiration, defined by positive tracheal aspirates for pepsin; and pulmonary infection. RESULTS: One hundred twenty patients were randomized and received the study drug (ulimorelin 62, metoclopramide 58). Mean APACHE II and SOFA scores were 21.6 and 8.6, and 63.3% of patients had medical reasons for ICU admission. Ulimorelin and metoclopramide resulted in comparable %DPPs over 5 days of treatment (median [Q1, Q3]: 82.9% [38.4%, 100.2%] and 82.3% [65.6%, 100.2%], respectively, p = 0.49). Five-day rates of feeding success were 67.7% and 70.6% when terminations unrelated to feeding were excluded, and there were no differences in any secondary outcomes or adverse events between the two groups. CONCLUSIONS: Both prokinetic agents achieved similar rates of feeding success, and no safety differences between the two treatment groups were observed.


Assuntos
Nutrição Enteral/normas , Compostos Macrocíclicos/normas , Metoclopramida/normas , APACHE , Adulto , Idoso , Antieméticos/normas , Antieméticos/uso terapêutico , Canadá , Estado Terminal/terapia , Método Duplo-Cego , Nutrição Enteral/métodos , Nutrição Enteral/estatística & dados numéricos , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Compostos Macrocíclicos/uso terapêutico , Masculino , Metoclopramida/uso terapêutico , Pessoa de Meia-Idade , Países Baixos , Escores de Disfunção Orgânica , Espanha , Estados Unidos
19.
Int J Mol Sci ; 20(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934667

RESUMO

Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a µ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.


Assuntos
Grelina/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Benzamidas/farmacologia , Eritromicina/administração & dosagem , Eritromicina/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Gastroparesia/sangue , Gastroparesia/induzido quimicamente , Gastroparesia/tratamento farmacológico , Gastroparesia/fisiopatologia , Grelina/sangue , Humanos , Loperamida/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Morfolinas/farmacologia , Período Pós-Prandial , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Estômago/efeitos dos fármacos , Estômago/patologia , Estômago/fisiopatologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia
20.
J Pharmacol Exp Ther ; 370(1): 35-43, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028106

RESUMO

KBP-088 (KeyBiosciencePeptide 088) is a potent dual amylin and calcitonin receptor agonist (DACRA). DACRAs are known to elicit potent activity in terms of typical amylin-induced responses, such as reducing food intake and body weight. However, to what extent amylin infusion can mimic the effects of the dual agonist KBP-088 is unknown. We studied the effect of acute dosing with KBP-088 (5 µg/kg) and rat amylin (100, 300, and 1000 µg/kg) and subsequently compared the chronic effect of KBP-088 (5 µg/kg per day) to increasing doses of rat amylin (100, 300, and 1000 µg/kg per day) delivered by continuous subcutaneous infusion, in high-fat diet (HFD) fed Long-Evans rats. Furthermore, acute amylin sensitivity was investigated. Single dose KBP-088 (5 µg/kg) potently reduced acute food intake for a prolonged period compared with amylin (100, 300, and 1000 µg/kg), confirming the difference in potency. Independent of dose, chronic amylin administration (100, 300, and 1000 µg/kg per day) was less effective than KBP-088 (5 µg/kg per day) in inducing body weight loss (15% with KBP-088, and 5%, 9%, and 8% with amylin, vehicle corrected) and reducing overall adiposity in HFD rats. Moreover, KBP-088 improved oral glucose tolerance with significantly reduced insulin levels (80% reduction) that were better than all doses of amylin (68%, 53%, and 7% reduction). Acute amylin sensitivity was independent of the chronic treatment. Dual activation of amylin and calcitonin receptors by KBP-088 is superior to amylin in reducing body weight and improving glucose tolerance, indicating a role for the calcitonin receptor.


Assuntos
Agonistas dos Receptores da Amilina/farmacologia , Peso Corporal/efeitos dos fármacos , Resistência à Insulina , Receptores da Calcitonina/agonistas , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
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